Inflammation is a complex biological response to pathogens, cell damage, and/or biological irritants. Inflammation may help an organism remove injurious stimuli, and initiate the healing process for the tissue, and is normally tightly regulated by the body. However, inappropriate or unchecked inflammation can also lead to a variety of disease states, including diseases such as hay fever, atherosclerosis, arthritis (rheumatoid, bursitis, gouty arthritis, polymyalgia rheumatic, etc.), asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, nephritis, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, transplant rejection, vasculitis, myocarditis, colitis, etc. In autoimmune diseases, for example, the immune system inappropriately triggers an inflammatory response, causing damage to its own tissues.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
The nervous system, and particularly the Vagus nerve, has been implicated as a modulator of inflammatory response. The Vagus nerve is part of an inflammatory reflex, which also includes the splenic nerve, the hepatic nerve and the trigeminal nerve. The efferent arm of the inflammatory reflex may be referred to as the cholinergic anti-inflammatory pathway. For example, Tracey et. al., have previously reported that the nervous system regulates systemic inflammation through a Vagus nerve pathway. This pathway may involve the regulation of inflammatory cytokines and/or activation of granulocytes. Thus, it is believed that appropriate modulation of the Vagus nerve (or other portions of the inflammatory reflex) may help regulate inflammation. Inhibition of the inflammatory reflex is described more fully in U.S. Pat. No. 6,610,713, filed on May 15, 2001 and titled “INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY CHOLINERGIC AGONISTS AND VAGUS NERVE STIMULATION”; pending U.S. patent application Ser. No. 11/807,493, filed on Feb. 26, 2003 and titled “INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY STIMULATION OF BRAIN MUSCARINIC RECEPTORS”; pending U.S. patent application Ser. No. 10/446,625, with a priority date of May 15, 2001 and titled “INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY CHOLINERGIC AGONISTS AND VAGUE NERVE STIMULATION”; and pending U.S. patent application Ser. No. 11/318,075, filed on Dec. 22, 2005 and titled “TREATING INFLAMMATORY DISORDERS BY ELECTRICAL VAGUS NERVE STIMULATION.” This provisional patent application may also be related to pending U.S. Provisional Patent Application Ser. No. 60/968,292, titled “DEVICES AND METHODS FOR INHIBITING GRANULOCYTE ACTIVATION BY NEURAL STIMULATION”, and Ser. No. 60/982,681, titled “TRANSCUTANEOUS VAGUS NERVE STIMULATION REDUCES SERUM HIGH MOBILITY GROUP BOX 1 LEVELS AND IMPROVES SURVIVAL IN MURINE SEPSIS”. Each of these patent and pending applications is herein incorporated by reference in its entirety.
A system for stimulating one or more nerves of the inflammatory reflex may include one or more electrical leads which may be implanted acutely or chronically, and may be positioned adjacent or in contact with the Vagus nerve or other nerves of the inflammatory reflex, and particularly the cholinergic anti-inflammatory reflex.
Unfortunately, stimulation of the inflammatory reflex is made difficult by artifacts and/or side-effects of stimulation. Most stimulation (neurostimulation) devices target neurons or muscles with electrodes that generate current to activate these organs. Ideally, such devices should stimulate only the target tissue or organ. Even more ideally, the stimulation of the target should be precise enough to avoid collateral stimulation. Furthermore, the stimulation should evoke the desired effect, without triggering other effects. In practice, localized stimulation has proven very difficult, and practically unrealizable. Unintentional stimulation of collateral organs from non-specific electrodes can be detrimental enough to prevent treatment and/or reduce the efficacy of treatment by requiring suboptimal stimulation.
Furthermore, the in-vivo stimulation environment may be very non-homogenous in electrical conductivity and organ activation characteristics (e.g. fiber diameter). The practical significance of this non-homogeneity is that positional changes in the stimulating electrodes can shift the path of the activating current, or change the characteristics of the stimulating current itself, such as the pulse width, rate, polarity, asymmetry, or the like. Control of electrode position and stimulation current characteristics is therefore critical for the success of neurostimulation therapies, particularly those in which collateral stimulation is an issue. Described herein are device and methods for optimal positioning of the electrode during surgery and optimization of stimulation parameters.
Currently available systems for stimulating nerves of the inflammatory reflex such as the Vagus nerve are generally not appropriate for stimulation of the Vagus nerve to regulate inflammation, because they would either be ineffective for inhibiting inflammation, or because they would result in undesirable side-effects. The configuration of the electrodes and stimulators, including the configuration of the stimulating electrodes of the electrical leads, in conjunction with the level, duration and frequency of stimulation, are critical to inhibiting or modulation of the inflammatory response appropriately (e.g., without desensitizing the inflammatory reflex).
For example, US Patent Application publication numbers 2006/0287678, US 2005/0075702, and US 2005/0075701 to Shafer describe a device and method of stimulating neurons of the sympathetic nervous system, including the splenic nerve to attenuate an immune response. Similarly, US Patent Application publication numbers 2006/0206155 and 2006/010668 describe stimulation of the Vagus nerve by an implanted electrode. US Patent Application publication number 2007/0027499 describes a device and method for treating mood disorders using electrical stimulation. US Patent Application publication number 2006/0229677 to Moffitt et al. describes transvascularly stimulating a nerve trunk through a blood vessel. U.S. Pat. No. 7,269,457 to Shafer et al. also describes a system for vagal nerve stimulation with multi-site cardiac pacing. All of these published patent applications and issued patents describe systems and methods for stimulating nerves, including the Vagus nerve. However, none of these publications teach or suggest stimulating the inflammatory reflex, including the Vagus nerve, using a system or method that would prevent desensitization of the inflammatory reflex, and would avoid undesirable effects or artifacts, such as muscle twitch or seizures, pain, cardiac effects (e.g., increase heart rate, etc.), hoarseness, or the like.
In practice, when a surgeon is inserting an electrode, the position of the electrode is necessarily crude, since implantation is often done via catheter or other minimally-invasive techniques, or done using indirect imaging techniques. Thus, it is often difficult for a doctor to precisely implant an electrode. In addition, we have found that the correct placement of an electrode may vary based on patient variability. This means that what an optimal position in one patient (e.g., a certain proximity to the vagus nerve) may be sub-optimal or non-functional in another patient. Thus, although stimulation systems, including those described above, may be applied by a surgeon using a known protocol, such insertion does not usually result in minimal stimulation artifact, particularly relative to the desired effect. To correct for this, stimulation levels may simply be increased (e.g., increasing the intensity or frequency) to attain a desired stimulation, often at the expense of an increased artifact or side-effect. Further, even when a stimulation electrode is implanted using a “trial and error” technique, it may be overly difficult or costly to examine the stimulation artifact in determining the optimal position, particularly in any reliable, reproducible manner.
Thus, there is a need for electrical leads and systems that include electrical leads are configured to appropriately modulate the inflammatory reflex without causing undesirable side effects or artifacts due to the stimulation.